The role of oxidative stress in major depressive disorder: Therapeutic approaches with antioxidants - a literature review

Authors

DOI:

https://doi.org/10.33448/rsd-v15i2.50646

Keywords:

Oxidative Stress, Major Depressive Disorder, Antioxidants, Depression.

Abstract

Major Depressive Disorder (MDD) is a psychiatric condition characterized by prolonged episodes of a combination of symptoms such as depressed mood and loss of interest. It may be triggered or intensified by various factors, among which oxidative stress and its associated chemical dysregulations stand out. The objective of this review is to explore antioxidant therapeutic approaches with the potential to contribute to the improvement of mental health in patients with Major Depressive Disorder through modulation of physiological antioxidant functioning. The review was conducted using the PubMed, Scielo, and LILACS databases, based on the following DeCS terms: ("oxidative stress" or "oxidative injury" or "oxidative cleavage") and ("depression" or "major depressive disorder"), resulting in 73 articles for analysis, of which 15 were included in this review after applying exclusion criteria in two stages. The analyzed studies highlight the effectiveness of different antioxidant interventions in reducing oxidative stress markers associated with depression. Among these approaches, the use of pharmacological agents such as N-acetylcysteine and thymoquinone, natural extracts such as Caesalpinia pulcherrima and ayahuasca, as well as supplementation with probiotics and fatty acids (omega-3, 6, and 9), are noteworthy. Positive effects were also observed from non-pharmacological strategies such as the adoption of antioxidant-rich diets, physical exercise, and repetitive transcranial magnetic stimulation. These interventions demonstrated antidepressant potential by modulating oxidative stress, although further studies are needed to assess their long-term efficacy.

References

American Psychiatric Association. (2023). Manual diagnóstico e estatístico de transtornos mentais: DSM-5-TR (Texto revisado) (5ª ed.) [E-book]. ArtMed. https://integrada.minhabiblioteca.com.br/reader/books/9786558820949/

Bhatt, S., Nagappa, A. N., & Patil, C. R. (2020). Role of oxidative stress in depression. Drug Discovery Today, 25(7), 1270–1276. https://doi.org/10.1016/j.drudis.2020.05.001

Brasil. Ministério da Saúde. (2022). Relatório de análise de impacto regulatório. Ministério da Saúde. https://bvsms.saude.gov.br/bvs/saudelegis/doc_tec/27.06.2022%20_%20PRT%20GM%201836.2022.pdf

Correia, A. S., Cardoso, A., & Vale, N. (2023). Oxidative Stress in Depression: The Link with the Stress Response, Neuroinflammation, Serotonin, Neurogenesis and Synaptic Plasticity. Antioxidants, 12(2), 470. https://doi.org/10.3390/antiox12020470

Crossetti, M. G. O. (2012). Revisão integrativa de pesquisa na enfermagem o rigor cientifico que lhe é exigido. Rev Gaúcha Enferm. 33(2):8-9. https://www.scielo.br/j/rgenf/a/9TrSVHTDtDGhcP5pLvGnt5n/?format=pdf&lang=pt.

Dhingra, D., & Deepak. (2021). Antidepressant-like activity of ethanol extract of leaves of Caesalpinia pulcherrima in unstressed and stressed mice. Brazilian Journal of Pharmaceutical Sciences, 57, 18891. https://doi.org/10.1590/s2175-97902020000418891

Djuricic, I.; Calder, P. C. (2021). Beneficial outcomes of omega-6 and omega-3 polyunsaturated fatty acids on human health: an update for 2021. Nutrients, 13 (7), 2421. https://doi.org/10.3390/nu13072421

Dotson, V. M., McClintock, S. M., Verhaeghen, P., Kim, J. U., Draheim, A. A., Syzmkowicz, S. M., Gradone, A. M., Bogoian, H. R., & Wit, L. D. (2020). Depression and Cognitive Control across the Lifespan: a Systematic Review and Meta-Analysis. Neuropsychology Review, 30, 461-476. https://doi.org/10.1007/s11065-020-09436-6

Filatova, E. V., Shadrina, M. I., & Slominsky, P. A. (2021). Major Depression: One Brain, One Disease, One Set of Intertwined Processes. Cells, 10(6), 1283. https://doi.org/10.3390/cells10061283

Harsanyi, S., Kupcova, I., Danisovic, L., Klein, M (2022). Selected biomarkers of depression: what are the effects of cytokines and inflammation?. International journal of molecular sciences, v. 24, n. 1, p. 578. https://doi.org/10.3390/ijms24010578

Hu, y., Cong, Q., Jia, X., Zhua, Q., Zheng, C., Ali, T., Lia, S., Liang, R. & Feng, J. (2026). P2Y6 receptor blockade promotes depression-like symptoms through oxidative stress and impaired autophagy. Free Radical Biology and Medicine, 242, 203-219. 2026. https://doi.org/10.1016/j.freeradbiomed.2025.10.268

Kanaan, R. A., Oliver, G., Dharan, A., Sendi, S., Maier, A., Mohebbi, M., Ng, C., Back, S. E., Kalivas, P., & Berk, M. (2023). A multi-centre, double-blind, 12-week, randomized, placebo-controlled trial of adjunctive N-Acetylcysteine for treatment-resistant PTSD. Psychiatry Research, 327, 115398. https://doi.org/10.1016/j.psychres.2023.115398

Khalatbari Mohseni, G., Ramezani, M., Pasdar, Y., & Khodarahmi, M. (2023). Effects of N‐acetylcysteine on oxidative stress biomarkers, depression, and anxiety symptoms in patients with multiple sclerosis. Neuropsychopharmacology Reports, 43(3), 382–390. https://pubmed.ncbi.nlm.nih.gov/37386885/

Kouchaki, E., Rafiei, H., Ghaderi, A., Azadchehr, M. J., Safa, F., Omidian, K., Khodabakhshi, A., Vahid, F., Rezapoor-Kafteroodi, B., Banafshe, H.-R., & Safa, N. (2024). Effects of crocin on inflammatory biomarkers and mental health status in patients with multiple sclerosis: A randomized, double-blinded clinical trial. Multiple Sclerosis and Related Disorders, 83, 105454. https://doi.org/10.1016/j.msard.2024.105454

Krittanawong, C., Maitra, N. S., Qadeer, Y. K., Wang, Z., Fogg, S., Storch, E. A., Celano, C. M., Huffman, J. C., Jha, M., Charney, D. S., & Lavie, C. J. (2023). Association of depression and cardiovascular disease. The American Journal of Medicine, 136(9), 881-895. https://doi.org/10.1016/j.amjmed.2023.04.036

Kunugi, H (2023) . Depression and lifestyle: Focusing on nutrition, exercise, and their possible relevance to molecular mechanisms. Psychiatry and clinical neurosciences, v. 77, n. 8, p. 420-433. https://doi.org/10.1111/pcn.13551

Kuzay, D., Dileköz, E., & Özer, Ç. (2022). Effects of thymoquinone in a rat model of reserpine-induced depression. Brazilian Journal of Pharmaceutical Sciences, 58, e19847. https://doi.org/10.1590/s2175-97902022e19847

Li, H., Ren, J., Li, Y., Wu, Q., & Wei, J. (2023). Oxidative stress: The nexus of obesity and cognitive dysfunction in diabetes. Frontiers in Endocrinology, 14, 1134025. https://doi.org/10.3389/fendo.2023.1134025

Li, X., Xu, R., Zhang, D., Cai, J., Zhou, H., Song, T., Wang, X., Kong, Q., Li, L., Liu, Z., He, Z., Tang, Z., Tan, J., & Zhang, J (2025). Baicalin: a potential therapeutic agent for acute kidney injury and renal fibrosis. Frontiers in Pharmacology, v. 16, p. 1511083. https://pmc.ncbi.nlm.nih.gov/articles/PMC11795133/

Lu, Z., Pu, C., Zhang, Y., Sun, Y., Liao, Y., Kang, Z., Feng, X., & Yue, W. (2022). Oxidative Stress and Psychiatric Disorders: Evidence from the Bidirectional Mendelian Randomization Study. Antioxidants, 11(7), 1386. https://doi.org/10.3390/antiox11071386

Molavi, N., Rasouli-Azad, M., Mirzaei, H., Matini, A. H., Banafshe, H. R., Valiollahzadeh, M., Hassanzadeh, M., Saghazade, A. R., Abbaszadeh-Mashkani, S., Mamsharifi, P., & Ghaderi, A. (2022). The Effects of Probiotic Supplementation on Opioid-Related Disorder in Patients under Methadone Maintenance Treatment Programs. International Journal of Clinical Practice, 2022 (1), 1–10. https://doi.org/10.1155/2022/1206914

Oliveira, N. G. de, Teixeira, I. T., Theodoro, H., & Branco, C. S. (2019). Dietary total antioxidant capacity as a preventive factor against depression in climacteric women. Dementia & Neuropsychologia, 13(3), 305–311. https://doi.org/10.1590/1980-57642018dn13-030007

Oppedisano, F.; Macri, R.; Gliozzi, M.; Musolino, V.; Carresi, C.; Maiúolo, J.; Bosco, F.; Núcera, S.; Zito, M. C.; Guarnieri, L; Scarano, F.; Nicita, C.; Coppoletta, A. R.; Ruga, S.; Scicchitato, M.; Mollace, R.; Palma, E.; & Mollace, V. (2020). The anti-inflammatory and antioxidant properties of n-3 PUFAs: Their role in cardiovascular protection. Biomedicines, 8 (9), 306. https://doi.org/10.3390/biomedicines8090306

Orsolini, L., Latini, R., Pompili, M., Serafini, G., Volpe, U., Vellante, F., Fornaro, M., Valchera, A., Tomasetti, C., Fraticelli, S., Alessandrini, M., La Rovere, R., Trotta, S., Martinotti, G., Di Giannantonio, M., & De Berardis, D. (2020). Understanding the Complex of Suicide in Depression: from Research to Clinics. Psychiatry Investigation, 17(3), 207. https://doi.org/10.30773/pi.2019.0171

Ozkan, B. N., Bozali, K., Boylu, M. E., Velioglu, H. A., Aktas, S., Kirpinar, I., & Guler, E. M. (2024). Correction: Altered blood parameters in “major depression” patients receiving repetitive transcranial magnetic stimulation (rTMS) therapy: a randomized case-control study. Translational Psychiatry, 14(1), 282. https://doi.org/10.1038/s41398-024-02999-5

Pereira, A. S. et al. (2018). Metodologia da pesquisa científica. Editora da UFSM. https://repositorio.ufsm.br/bitstream/handle/1/15824/Lic_Computacao_Metodologia-Pesquisa-Cientifica.pdf?sequence=1.

Pettorruso, M., d’Andrea, G., Martinotti, G., Cocciolillo, F., Miuli, A., Di Muzio, I., Collevecchio, R., Verrastro, V., De-Giorgio, F., Janiri, L., di Giannantonio, M., Di Giuda, D., & Camardese, G. (2020). Hopelessness, Dissociative Symptoms, and Suicide Risk in Major Depressive Disorder: Clinical and Biological Correlates. Brain Sciences, 10(8), 519. https://doi.org/10.3390/brainsci10080519.

Rabiei, Z., & Setorki, M. (2019). Effect of ethanol Adiantum capillus-veneris extract in experimental models of anxiety and depression. Brazilian Journal of Pharmaceutical Sciences, 55, e18099. https://www.scielo.br/j/bjps/a/pfJGcnDkxdZwvXdfHMHkrxS/?lang=en&format=pdf

Risemberg, R. I. C. et al. (2026). A importância da metodologia científica no desenvolvimento de artigos científicos. E-Acadêmica. 7(1), e0171675. https://eacademica.org/eacademica/article/view/675.

Sarno, E., Moeser, A. J., & Robison, A. J. (2021). Neuroimmunology of depression. In Advances in pharmacology (Vol. 91, pp. 259–292). Academic Press. https://www.sciencedirect.com/science/article/abs/pii/S1054358921000181

Silva, L. A. D., Tortelli, L., Motta, J., Menguer, L., Mariano, S., Tasca, G., Silveira, G. D. B., Pinho, R. A., & Silveira, P. C. L. (2019). Effects of aquatic exercise on mental health, functional autonomy and oxidative stress in depressed elderly individuals: A randomized clinical trial. Clinics, 74, e322. https://doi.org/10.6061/clinics/2019/e322

Silva Neto, L. B., Chaves Filho, A. J. M., Casadevall, M. Q. F. C., Azevedo, O. G. R., Macêdo, D. S., & Vasconcelos, P. R. L. (2022). Ad libitum consumption of milk supplemented with omega 3, 6, and 9 oils from infancy to middle age alters behavioral and oxidative outcomes in male mice. Brazilian Journal of Medical and Biological Research, 55, e12195. https://doi.org/10.1590/1414-431X2022e12195

Snyder, H. (2019). Literature review as a research methodology: An overview and guidelines. Journal of Business Research. 104, 333-9. https://doi.org/10.1016/j.jbusres.2019.07.039.

Sobin, C., & Sackeim, H. (2025). The psychomotor symptoms of depression. American Journal of Psychiatry. https://scholarworks.utep.edu/cgi/viewcontent.cgi?article=1145&context=pub_health_papers

Velichkov, M., Zsofia, B., Reekum, C. M. van, & Williams, C. M. (2024). A biphasic response to blueberry supplementation on depressive symptoms in emerging adults: a double-blind randomized controlled trial. European Journal of Nutrition (Print), 63(4), 1071-1088. https://doi.org/10.1007/s00394-023-03311-9

Xavier, J., Farias, C. P., Soares, M. S. P., Silveira, G. de O., Spanevello, R. M., Yonamine, M., Gamaro, G. D., Carvalho, H. W. de, & Cognato, G. de P. (2021). Ayahuasca prevents oxidative stress in a rat model of depression elicited by unpredictable chronic mild stress. Archives of Clinical Psychiatry (São Paulo), 48(2), 90–98. https://doi.org/10.15761/0101-60830000000286

Yaikwawong, M., Jansarikit, L., Jirawatnotai S., & Chuengsamarn, S. (2024) Curcumin reduces depression in obese patients with type 2 diabetes: A randomized controlled trial. Nutrients, 16 (15), 2414. https://pubmed.ncbi.nlm.nih.gov/39125295/.

Zhong, J., Li, G., Xu, H., Wang, Y., & Shi, M. (2019). Baicalin ameliorates chronic mild stress-induced depression-like behaviors in mice and attenuates inflammatory cytokines and oxidative stress. Brazilian Journal of Medical and Biological Research

Published

2026-02-15

Issue

Section

Review Article

How to Cite

The role of oxidative stress in major depressive disorder: Therapeutic approaches with antioxidants - a literature review. Research, Society and Development, [S. l.], v. 15, n. 2, p. e5615250646, 2026. DOI: 10.33448/rsd-v15i2.50646. Disponível em: https://www.rsdjournal.org/rsd/article/view/50646. Acesso em: 1 mar. 2026.